Strategies for thinning the blood are important in the treatment and management of atrial fibrillation as risk of stroke is a serious consideration. The pooling of blood in an atrium that is not contracting properly can lead to the formation of a clot within the left atrium, specifically in a recess called the left atrial appendage. Should this clot be dislodged, it can pass through the left ventricle, make its way to the brain and cause a stroke. Thinning the blood reduces that risk.

Before considering situations in which it is important to thin the blood, let’s look at how a blood clot forms and understand the coagulation cascade, both important factors in understanding atrial fibrillation treatment.

protection

The body needs to be able to protect itself if there is damage to the circulation. If bleeding from a cut or a scratch is not stopped, the person will bleed to death. The mechanism that stops us bleeding to death is the formation of a blood clot, or thrombosis.

The coagulation cascade, in its simplest terms, has two major components that give rise to the formation of a clot. One component is the small particles that come from the bone marrow and are called platelets. They don’t have a nucleus, so they are not ‘complete’ cells but they are part of what forms a clot. The other element, in conjunction with platelets, is a strong cross-bridging strand protein called fibrin, the scaffold of the clot formation.

When there is damage to the blood vessel, proteins and receptors that are not normally exposed to the blood circulation become exposed. With this, platelets come into contact with receptors with which they normally would not have contact. Those proteins and receptors activate platelets, causing changes which lead to preparation for forming a clot. So that fibrin is formed to bind with those platelets, a cascade of different factors is started. That cascade is called the coagulation cascade. The clot formation occurs through the activation of platelets which results in the platelets interacting with fibrin, after the fibrin has been generated through the coagulation cascade. In atrial fibrillation, the main driver is stasis of blood, or stagnation of the normal flow of blood, within the left atrial appendage, allowing clotting factors to interact in a way that is just not possible when they are in free-flowing blood within the circulation.

Fibrin and platelets together form the clot that blocks or seals the blood vessel.

What then stops the clot progressing until all the blood congeals?

So that the whole body doesn’t end up as one big clot, there are also factors generated that limit the progression of a clot. These factors are called the fibrinolytic system. As the body is forming a clot, it is also producing factors that prevent the clot from extending too far.

In some medical situations, such as atrial fibrillation and other heart- related matters, the body does not want a clot to form as it can cause a more serious problem, such as a stroke or a heart attack. To help stop a clot forming, anti-coagulation therapies are implemented, keeping in mind two major risks: the possibility of stroke in the future and the likelihood of bleeding.

It is important to understand something about the clot-forming pathway as it helps patients understand where and why medications work. For example, aspirin and clopidogrel are used to dampen down platelet function. Warfarin, heparin and the NOACs are used to work on the coagulation cascade. These different agents act in different locations within the clotting cascade, essentially to decrease the production of the end product, the fibrin, and so reduce the possibility of a clot forming.

A CLOSER LOOK
KEEPING SCORE: CHA₂DS₂-VASc and HAS-BLED

There are two significant considerations that come into play when deciding on anticoagulation therapy:
•    risk of stroke in the future
•    risk of bleeding.

A risk score calculator has been developed for each of these considerations.

People who suffer Cardiac failure, high blood pressure (Hypertension), increasing Age and Diabetes (CHAD) all have an increased risk of stroke if they also have atrial fibrillation. A tool has been formulated in which these parameters receive a score. The tally of those scores is then used in management decisions. Over time, the original CHAD score has been modified with more information being added.

Today’s CHA₂DS₂-VASc score offers extra options: age variability (it breaks down age groups into lower, intermediate and higher risks), the patient’s sex (women run a higher risk of stroke), and it also adds, as a consideration, previous stroke or vascular disease within the arterial system. As these parameters provide a likelihood of the risk of stroke in the future, the score is used in decision-making regarding the need for anticoagulation therapy.

Should the patient need anticoagulation therapy, the question then needs to be asked, How safe is anticoagulant therapy for that patient? with the consideration here being the risk of bleeding.

Here, we look at another score, HAS-BLED: Hypertension, Abnormal renal or liver function, previous Stroke, previous Bleeding problems principally from the gut, Labile control of warfarin (labile INR), Elderly (over 65 years of age), Drugs or alcohol. As with the CHA₂DS₂-VASc score, each parameter is given a score, with the tally indicating the risk of bleeding for that individual.

The HAS-BLED score was developed before the NOAC agents became widely available and so the labile INR can be removed from the score if a NOAC is to be used. However, if that is done, the medical practitioner needs to consider renal function as this is known to be a driver for risk of bleeding. Adequate renal function is needed for metabolism of the NOACs.

The CHA₂DS₂-VASc score and the HAS-BLED score are married to help to make a management decision for our patient based on the balance of where we think those scores lie. We try to weigh up the risks for the person the best we can. You will remember Gran from the introduction. In her case, the HAS-BLED score, or the risk of bleeding, was so high from the difficulties with warfarin that it outweighed the CHAD score, or the risk of having a stroke, and this was reflected in her treatment.

The risks need to be reviewed periodically as both scores can change with time. For example, the age component will increase, the cardiac failure component could change, high blood pressure could be brought under control or develop.

Although these scores are dynamic, they give us a good understanding for trying to mitigate future risk of stroke and future risk of bleeding for the patient.

now and later

There are two different situations in which thinning the blood to reduce the risk of stroke can be considered: the acute setting when somebody first presents, and in the longer term.

In the acute setting, historically, drugs such as heparin and clexane which act on factor 10 in the clotting cascade, have been used. Both these drugs work effectively and can be given as injections as soon as a person presents at an accident and emergency department. The treating doctors will address atrial fibrillation by slowing the person’s heart rate and dealing with the risk of stroke, simultaneously.

Heparin and clexane work well in this acute situation. However, because they are administered as injections either into the skin or into the vein, they are generally not practical, long-term solutions. Who would want ongoing injections as a treatment if there is a pill that can be swallowed?

warfarin

Warfarin is the blood thinner with which people are most familiar, at least by name. Some of my patients often refer to warfarin as ‘rat killer’ as it is the active ingredient in the substance used as rat poison for many, many years.

In our bodies, warfarin blocks the action of vitamin K which is used by the liver to produce the clotting factors. Warfarin is not a good agent in the acute setting as it can take several days for the proteins that it blocks to be cleared from the system and therefore have its full effect. It also needs adjustment from patient to patient and over time.

new agents, NOACs

Another option is the use of new agents on the market, Direct or Novel Oral AntiCoagulants, often referred to as DOACs or NOACs. These agents act directly on the coagulation cascade and each acts quickly. Most conveniently, these medications do not need regular blood tests to monitor their effect. However, in Australia specific criteria need to be met for them to be prescribed and funded by the Commonwealth Government14. NOACs include the drugs apixaban, dabigatran and rivaroxaban.

With the advent of these new agents, my practice now is to use them as soon as possible, including on a person’s arrival at the accident and emergency department, unless there is any clear contraindication of their use. Within hours we see a result; blood thinning occurs. They can be used long-term and the NOACs do not require regular monitoring as does warfarin.

The limitation with these NOACs is that the patient needs to have good, or at least reasonable, renal function so that the drugs don’t build up in the body and cause toxicity problems. In the situation in which the patient has significantly reduced renal function and will require long-term anticoagulation, then warfarin is the tried and tested option. While it does need to be monitored and adjusted on a regular basis, it works.

The NOACs are also specifically recommended for patients who have no significant heart valve problems. If a patient has a narrowing of the mitral valve, slowing flow between the atrium and the ventricle, or has had a mechanical heart valve replacement of any sort, even in the setting of good renal function, warfarin is the appropriate agent. An abnormality of the valves of this type is referred to as valvular AF, and NOACs are not recommended for this group of patients.

The NOAC agents have similarities and differences.

Apixaban and rivaroxaban both work through factor 10 which is the same factor through which heparin and clexane work. There is a sense within the medical fraternity that apixaban is slightly gentler for the older age group, particularly for people with slight renal impairment. Practical application suggests that the convenience of rivaroxaban as a single daily dose is preferred by patients.

Dabigatran works through factor 2. The outcomes are very similar to using apixaban and rivaroxaban. Dabigatran has a reversal agent, which can be an important factor in decision-making around the selection of the direct oral anticoagulant the doctor might choose for a person’s atrial fibrillation.
Apixaban and rivaroxaban both have a reversal agent under development and it is likely to be available soon. A reversal agent is significant should the anticoagulation need to be stopped quickly, especially in an emergency situation.

A CLOSER LOOK
WARFARIN

The adjustment of warfarin is a ‘Goldilocks’ process. We don’t want the blood too thin (from too much warfarin), nor do we want the blood too thick (not enough warfarin). We want it just right.

We arrive at ‘just right’ by measuring the time it takes for the blood to form a clot in a special laboratory test. This test has been standardised worldwide and is called the International Normalised Ratio (INR). This means you can have your INR checked anywhere in the world and know how to deal with the result.

When thinning blood for atrial fibrillation, we generally aim for an INR of over two and less than three. Too low will not be effective and too high will run an unacceptably high risk of bleeding.

Having an INR under two or over three is called being out of therapeutic range, that is, not in the range required for effective and safe therapeutic effect.

The way we achieve therapeutic warfarin levels, when someone is starting to use the drug, is generally to load the patient with highish doses for a couple of days, to start the blood thinning effect, and then check the effect using a blood test. The process then becomes one of increasing or lowering the dose to achieve the desired INR. This is called ‘titrating’ the dose and it can often take a few weeks before the correct level is achieved.

The objective is to find the ideal dose for the patient and then check the INR on a regular basis, perhaps monthly for a stable patient. Anyone on warfarin will need to become familiar with regular blood tests for checking their INR.

Recently, hand-held home devices have become available, allowing patients to adjust their own warfarin dose based on this home testing. This is a great solution for some people.

It is also really important to remember that the effect of warfarin may change based on external factors. Illness or, perhaps even more importantly, the addition of other drugs, can interact with warfarin and alter the INR, as can some foods. Change in a patient’s clinical situation requires close attention to the INR to avoid complications.

ANSWERING IMPORTANT QUESTIONS
WHAT IF I CAN’T TOLERATE WARFARIN OR NOACS?

A situation can arise when a patient may have clear reasons for not taking blood-thinning medications but still needs protection from the risk of stroke associated with AF. For example, a patient who may have an abnormality of blood vessels in the brain which could be at risk of bleeding, cannot be on a blood thinner.

There is a possible solution. The recent development of a rather audacious idea that, if you can block off the left atrial appendage (the recess in the left atrium), preventing the stagnant pooling of blood there, then perhaps you can prevent the formation of a clot altogether.

Several randomised studies have occlusive device compared warfarin therapy with the use of an implanted left atrial occlusive device and found that the device worked just as well as warfarin. This means that, for really high-risk patients who just aren’t able to take blood-thinning medications, there may be an alternative.

HOW DO I COPE WITH RECURRENT BLEEDING?

Bleeding from the nose, called epistaxis, and bleeding from the bottom, called Per Rectal or PR bleeding, can be a real nuisance for some patients and each problem needs a solution.

I try to deal with the underlying problem: cautery to the lining of the nose and ligation of haemorrhoids for bleeding piles. If these don’t work then, perhaps, an alternate agent can be used, for example, warfarin to a NOAC, or a change of dose of the NOAC. This could be dabigatran 150 mg to 110 mg twice daily, rivaroxaban 20 mg to the 15 mg preparation, or maybe apixaban 5 mg to the 2.5 mg preparation.

The solution is a matter of finding a way that weighs risk against benefit and convenience against inconvenience.